Stiftung Tierärztliche Hochschule Hannover (TiHo)

Reversion of pneumolysin induced executioner caspase activation redirects cells to survival

Apoptosis is an indispensable mechanism for eliminating infected cells and activation of executioner caspases is considered as a point of no return. Streptococcus pneumoniae, the most common bacterial pathogen causing community-acquired pneumonia, induces apoptosis via its pore forming toxin pneumolysin, leading to rapid influxes of mitochondrial calcium [Ca 2+]m as well as fragmentation, loss of motility and membrane potential, which is accompanied by caspase-3/7 activation. Using machine-learning and quantitative live-cell microscopy, we identified a significant number of alveolar epithelial cells surviving such executioner caspase activation after pneumolysin attack. Precise single cell analysis revealed the [Ca 2+]m amplitude and efflux rate as decisive parameters for survival and death, which was verified by pharmacological inhibition of [Ca 2+]m efflux shifting the surviving cells towards the dying fraction. Taken together, we identified the regulation of [Ca 2+]m as critical for controlling the cellular fate under pneumolysin attack, which might be useful for therapeutic intervention during pneumococcal infection.


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